1. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
- Author
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Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W., Boland, Anne, Raybould, Rachel, Bis, Joshua C., Martin, Eden R., Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B., Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R., Olaso, Robert, Hoffmann, Per, Grove, Megan L., Vardarajan, Badri N., Hiltunen, Mikko, Noethen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, Forstner, Andreas J., Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L., Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A., Qu, Liming, Sanchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J., Zhao, Yi, Sanchez Garcia, Florentino, Denning, Nicola, Fornage, Myriam, Malamon, John, Deniz Naranjo, Maria Candida, Majounie, Elisa, Mosley, Thomas H., Dombroski, Beth, Wallon, David, Lupton, Michelle K., Dupuis, Josee, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B., Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D., Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H., Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L. Adrienne, Price, Nathan D., Hannequin, Didier, Frank-Garcia, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S., Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E., Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K., Pasquier, Florence, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Longstreth, W. T., Jr., Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Diez Fairen, Mnica, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Forte, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., Mckee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Munoz Fernadez, Carmen, Aladro Benito, Yoland, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux-, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, Schellenberg, Gerard D., Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W., Boland, Anne, Raybould, Rachel, Bis, Joshua C., Martin, Eden R., Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B., Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R., Olaso, Robert, Hoffmann, Per, Grove, Megan L., Vardarajan, Badri N., Hiltunen, Mikko, Noethen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, Forstner, Andreas J., Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L., Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A., Qu, Liming, Sanchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J., Zhao, Yi, Sanchez Garcia, Florentino, Denning, Nicola, Fornage, Myriam, Malamon, John, Deniz Naranjo, Maria Candida, Majounie, Elisa, Mosley, Thomas H., Dombroski, Beth, Wallon, David, Lupton, Michelle K., Dupuis, Josee, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B., Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D., Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H., Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L. Adrienne, Price, Nathan D., Hannequin, Didier, Frank-Garcia, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S., Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E., Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K., Pasquier, Florence, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Longstreth, W. T., Jr., Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Diez Fairen, Mnica, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Forte, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., Mckee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Munoz Fernadez, Carmen, Aladro Benito, Yoland, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux-, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D.
- Abstract
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 x 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 x 10(-8)) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p. Pro522Arg, P = 5.38 x 10(-10), odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p. Ser209Phe, P = 4.56 x 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p. Arg62His, P = 1.55 x 10(-14), OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
- Published
- 2017
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